The purpose of these experiments is to examine mechanisms which regulate cerebral microvascular permeability under normal and pathological conditions. The site and mechanism of disruption of the blood-brain barrier during pathological conditions remain controversial. I have completed experiments which suggest that veins are the primary site of disruption of the blood-brain barrier during acute hypertension and hyperosmolar arabinose. During acute hypertension, disruption of the venous blood-brain barrier was associated with an increase in pial venous pressure. Experiments are proposed to determine whether 1) rate of rise in venous pressure affects disruption of the venous blood-brain barier, 2) disruption of the blood-brain barrier during hyperosmolar arabinose and seizures is associated with an increase in pial venous pressure, and 3) disruption of the venous blood-brain barrier is associated with an increase in vesicular transport or with separation of endothelial tight junctions. Disruption of the blood-brain barrier during acute hypertension is reduced in genetically hypertensive rats. The mechanism of this protective effect is assumed to be related to hypertrophy of large cerebral arteries, protecting downstream arterioles and capillaries from an increase in pressure. I propose to determine whether 1) increases in pial venous pressure are attenuated in chronic hypertension, and 2) cerebral veins undergo hypertrophy during chronic hypertension and protect the venous blood-brain barrier during elevation of pial venous pressure. Oxygen radicals increase permeability in many vascular beds. In cerebral vessels, oxygen radicals dilate arterioles and damage endothelial cells. This effect is inhibited by enzymatic inhibitors of oxygen radicals. Oxygen radicals also are implicated as mediators of endothelial damage during acute hypertension. The proposed studies will determine whether 1) oxygen radicals alter permeability of the blood-brain barrier, and 2) oxygen radicals mediate disruption of the blood-brain barrier during acute hypertension. These experiments will provide new information in three areas: 1) the role of veins and venous pressure in disruption of the blood-brain barrier, 2) the mechanism of blood-brain barrier protection in chronic hypertension, and 3) the role of oxygen radicals in disruption of the blood-brain barrier.